薬理と治療

わが国の小児医薬品開発は，欧米にくらべて遅れている（ドラッグラグ）。米国では企業は原則として，小児の医薬品開発計画であるPediatric StudyPlan（ PSP）を成人の第Ⅱ相試験後に，EUでは，小児の医薬品開発計画であるPaediatric InvestigationalPlan（ PIP）を成人の第Ⅰ相試験後に，規制当局に提出することが法令で定められている。また，小児医薬品開発に対するインセンティブとして，新規医薬品については6 ヵ月の特許期間延長，希少疾病用医薬品に対しては2 年間の市場独占権，等が付与されることも法令で規定されている。これにより欧米では小児治験数が急激に増えている。欧州医薬品庁からの2017 年の報告1） によると，法令が制定された2007 年以降，小児医薬品・小児適応・小児製剤の承認数は急激に伸びている。さらに，小児臨床試験数が増加しているだけでなく，より大規模な試験も増えており，小児臨床試験ネットワークの構築なども進んでいる。

日本での小児医薬品開発を促進していくためには，小児治験を実施できる医療施設の体制整備を進める必要がある。国内の小児領域の医薬品開発数が少ないがゆえ，小児治験を経験している医師，医療スタッフ，治験事務職に至るまで小児医療施設での治験実施体制は盤石とはいえない状況である。また，治験をサポートするCRC においては，小児科領域の知識を持つ人材が少なく，各小児医療施設に配置されていないことも多かった。そんななか，小児治験や臨床研究の効率的な実施を目的として2010 年11 月に日本小児総合医療施設協議会（現一般社団法人日本小児総合医療施設協議会：JACHRI）加盟施設を中心に，全国規模での「小児領域に特化した治験ネットワーク」として小児治験ネットワーク（以下，小児NW）が設立され，2019 年9 月時点では，45 施設が加盟登録している。小児医療を取り巻く環境は，医薬品の「適応外使用」をはじめ多くの問題を抱えている。そのなかで小児NW は，子どもたちが安心できる小児医薬品等の開発促進を目指し，小児治験実施体制の構築により，治験依頼者と医療機関双方の負担軽減とコスト削減等を目指して活動している。

小さな子どもに服薬させた経験があるだろうか？軽い風邪くらいならおいしいシロップ剤を喜んで服用してくれたかもしれない。しかし，すでに疾病により調子が悪く機嫌も悪い患児はどうだろうか？あるいは慢性疾患で長期に服用しなければならない患児において，飲みにくい薬の服用はかなりの負担を強いることになる。ある５歳の男の子は小児がんとの闘病中，薬がうまく飲めなくて親子で毎日泣きながら本当に苦労されたそうだ1）。小さな子どもの場合，服薬に悪戦苦闘して１回に１時間以上を要することもある。筆者は製薬企業で16 年間製剤研究をしていたが，どうしても患者数が多い疾患に注目してしまい，少数のましてや子どもの意見を聞くことができていなかった。そこであらためて闘病中の子供たちに直接意見を聞いてみたところ，意外にもシロップは不評であった。「甘すぎる」「色を見ただけで吐き気がする」「量が多い」など。「１回で飲める少量がいい」「水にさっと溶ける粉薬がいい」「味もにおいもないほうがいい」と意見はさまざまだが，どうやらシロップは風邪薬など短期間の服用には向いているが，長期連用には適さないようであった。日本では，小児に使用される医薬品のうち約70％が，添付文書に小児の用法･用量が記載されていないことから，医師の裁量でやむを得ず適用外使用されており，小児用製剤まで用意されている製品は少ない。したがって，小児患者自身に剤形や味･におい，錠剤の粉砕など剤形変更を選択できる余地はほとんどないのが現状である。小児にとって薬の味や飲みやすさは，服薬できるかどうかにかかわる重要な問題であり，極端に言えば薬効と同等の意味があるにもかかわらず，なぜ小児用製剤は開発・上市されないのであろうか。

小児医薬品開発は，状況を改善するための医療政策が米国で施行されてからすでに20 年が経つが，成人と比較して遅れが目立つ。1997 年にFDAModernization Act（FDAMA）が制定され1），小児医薬品開発を行う企業へのインセンティブの付与が法律化された。また，1998 年にはPediatric Rule がU.S. Food and Drug Administration（FDA）から発表された2）。これによりFDA は製薬企業に，新薬や既承認薬で小児に必要なものについて，小児でも安全性や効果の評価を求めることができるようになった。その数年後Pediatric Ruleは一度却下されたが，小児医薬品開発の必要性は明らかであったことから，インセンティブを付与するFDAMA の基本的な要素を取り入れて，2002 年にBest Pharmaceuticals forChildren Act （BPCA）3） が，2003 年にはPediatricResearch Equity Act （PREA）4）が法制化され，小児医薬品開発を促進する原動力となった。BPCA は法の提供するメリットを製薬企業が認識することで，開発義務こそないものの小児医薬品開発研究の拡大への意欲を促進する機能を果たしている。一方，PREA は新薬を開発する企業に対してFDAが小児を対象とした研究を義務づけるというものである。開発する薬品の種類や目的によっては義務化の対象外とされる場合もあるが，時限立法であったBPCAとPREAは2012年にFDA Safety and InnovationAct 4）の制定により永久的な政策となった。Pediatric Rule やBPCA，PREA の法制化がこの20年でもたらした成果は大きい。というのも2020 年12 月1 日現在，854 の薬品の薬品添付文書の改訂がなされ，小児への処方と利用に関する情報が追加された5）。そして類似した政策を施行している国々も増えた6）。

Background　Several clinical trials have investigated the impact of olive-derived hydroxytyrosol（OHT）on the protection low density lipoprotein（LDL）from oxidative damages, but no systematic review was conducted. Objective　The objective was to perform a systematic review with meta-analysis of randomized, placebo-controlled trials of OHT to evaluate its impact on decrease blood oxidized LDL （oxLDL）in the healthy adults or adults with mild diseases. Method　A systematic literature search was conducted with scientific databases, register databases for clinical trials-systematic review, and common internet search-engines and done manually within scientific journals.　The primary outcome measure was values of blood oxLDL. A random-effects model was used to calculate the standardized mean difference and 95％ confidence interval（CI）as the difference between the mean for the treatment and placebo groups. Standard methods for assessing statistical heterogeneity and bias risk were used. The protocol for this study was registered to UMIN-CTR（No. UMIN000040080）. Result　Three studies met the inclusion criteria. The use of food containing OHT decreased level of blood oxLDL［standardized mean difference （SMD）：－0.26；95％ CI：－0.39, －0.12］.　Heterogeneity was not observed in the meta-analysis. Bias risk for body of evidence was rated as medium. Conclusion　This systematic review suggests that OHT decrease blood oxLDL in the healthy adults. However, it is required that further high-quality RCT trials are reported because publication bias cannot be ignored in this systematic review.

Background　It is known that 7,12-dimethylbenz（a）anthracene（DMBA）induces mammary tumors in rats, and SHN strain mice have a high potential for mammary carcinogenesis. Medroxyprogesterone acetate（MPA）has antiestrogenic and antigonadotropic activities, and tamoxifen（TAM）has agonistic and antagonistic activities for estrogen. The 5-fluorouracil derivative, UFT has been used as an oral anticancer drug. Thymidylate synthase（TS）and thymidine kinase（TK）, key enzymes in the de novo and salvage pathways for pyrimidine nucleotide synthesis, are highly active in rapidly proliferating tissues. Methods　We investigated the effects of MPA and TAM on DMBA-induced rat mammary tumors, and the effects of MPA and UFT on mammary carcinogenesis in SHN virgin mice. Results　MPA and TAM reduced the number of rat mammary tumors with reduction of plasma levels of estradiol and tissue TS and TK activities. However, MPA with estrogen slightly shortened the latent period of mouse mammary carcinogenesis. Long-term administrations of low-dose UFT lowered the number of hyperplastic alveolar nodules, which were representative preneoplastic states in mammary glands of mice, with decrease in both TS and TK activities, and high-dose UFT decreased total volume of mammary tumors with diminution of TS activity, but not TK, in SHN mice. Conclusions　MPA and TAM could suppress mammary carcinogenesis in rats, but MPA with estrogen might slightly hasten mammary carcinogenesis in mice. UFT might inhibit mammary carcinogenesis via the de novo pathway for pyrimidine nucleotide synthesis in mice.

Background　Langerhans cells, which are scattered in the epidermal squamous cell layer as dendritic cells, are suggested to play an important role for alleviation or healing of inflammation through their regulatory function for the dermal barrier. Especially, in atopic dermatitis, the deterioration of the dermal barrier function is suggested to be a serious factor, and the relationship between the function of Langerhans cells as a reinforcement of dermal barrier and atopic dermatitis is very interested. However, there has been neither any useful product which can induce remission of atopic dermatitis, nor any product which is focused on the epidermal Langerhans cells developed yet. Objective　To study the effects of PS, which is a unique complex of amino acids developed by us and has many good results for several dermatitis such as atopic dermatitis, on the epidermal Langerhans cells. Methods　One ％ hydrocortisone（HC）in 10 μL ethanol was applied twice daily for 5 days on the inner surface of the right ears of BALB/c mice（steroid-treatment）. Non-steroid- treatment （control）group of the mice was applied 10 μL ethanol. It was confirmed that the number of epidermal Langerhans cells（shown as MHC Class Ⅱ-positive cells in the epidermis area）is decreased in the murine ears of steroid-treatment groups as reported previously（Meingassner JG, et al. Br J Dermatol 2003; 149: 853-7）. In order to study the effects of PS, 10 μL of PS was applied once a day for 3 days, 9 days, 16 days, and 23 days on the inner surface of the murine right ears of steroid-treatment group. In the control group, 10 μL of saline was administered instead of PS. The murine ears in each group were gathered and their paraffin-embed samples were prepared. The number of MHC Class Ⅱ-positive cells in the epidermis area within 2000 μm from the top in the inner ear of each sample was counted as that of epidermal Langerhans cells. Also, the ear thickness and the square measure of the epidermis area within 2000 μm from the top in the inner ear were determined for each sample. Results　The lowered numbers of MHC Class Ⅱ-positive cells in steroid-treatment group murine ears were significantly increased in PS-applied group for 9 days and 23 days（P＜0.05）. Also, an increase tendency in the number for 16 days group was observed（P＝0.059）. The increase in the number in PS-applied group was PS-application time-dependent. The square measure of the epidermis area within 2000 μm from the top in the inner ear was significantly decreased by steroid-treatment（P＜0.05）, though the ear thickness of each group was unchanged. The decreased square measure of the epidermis area was recovered by PS-application time-dependently. The square measure of the epidermis area was significantly increased for 16 days and 23 days（P＜0.05）, and recovered to the level of that of non-steroid-treatment （control）group. Conclusion 　In summary, PS, which can induce remission of atopic dermatitis and other several dermatitis as reported before（Nishikori K, et al. J Am Acad Dermatol Abst 2010; 1308）, was shown to be able to increase the number of MHC Class Ⅱ-positive cells（suggesting the epidermal Langerhans cells）and recovered the shrunk epidermis area in murine ears of steroid-treatment group. This observation may be an epoch-making event in the present situation that there has been neither products which can induce remission of atopic dermatitis, nor is focused on the epidermal Langerhans cells.

Objectives　Lactobacillus paracasei K71（L. paracasei K71）has anti-allergic capacity such as T helper 1（Th1）polarization in mouse splenocytes and IgE level suppression in ovalbumin （OVA）-immunized mouse serum. We investigated the palliative effects of L. paracasei K71 intake on Japanese cedar（JC）pollen allergy in a randomized, double-blind, placebo-controlled, parallel-group trial in an environmental exposure unit（EEU）. Methods　Fifty subjects with JC pollen-specific IgE were enrolled in this trial. Subjects（n＝25 per group）were allocated randomly and ingested two tablets containing 50 mg（approximately 1×1011 bacteria）of L. paracasei K71（group A）or placebo（group P）daily for 8 weeks. Before and after intake period, subjects were exposed to JC pollen for 3 hours and answered a questionnaire about pollinosis symptoms in the EEU. The questionnaire was continued for 4 days after JC pollen exposure. Results　One subject withdrew, another met an exclusion criterion, and 48 subjects were included in the efficacy analysis. Number of nose blows（30 min）and nasal congestion score （30 and 60 min） in EEU were significantly suppressed in group A. Additionally, number of sneezes （day 2）and sore or scratchy throat score（day 3）after JC pollen exposure were significantly suppressed in group A. Conclusions　The results suggest that the continuous intake of L. paracasei K71 palliates nasal and throat discomfort during and after JC pollen exposure. （UMIN ID: 000037571）

Objective　This study aimed to verify the efficacy and safety of a test tablet containing dry powder of rice shochu distilled residue, skipjack tuna elastin, and tomato seed extract on the skin of healthy Japanese adults. Methods　A randomized, double-blind, placebo-controlled, parallel-group comparison trial was conducted from January 11 to June 12, 2020 among healthy Japanese adults with skin moisture problems. Twenty-eight subjects were randomly assigned to the active or placebo group. Subjects took two tablets（active or placebo）with water at breakfast for 12 weeks. Skin moisture content, transepidermal water loss（TEWL）, skin viscoelasticity, dermal evaluation, subjective symptoms for skin, and evaluation of safety（physical examination, urinalysis, blood tests）were conducted. Results 　There were two subjects in the active group and one in the placebo group who received no intervention after allocation, so the efficacy analysis was set as the full analysis for 26 subjects in the test group and 27 in the placebo group. Although there were no findings of efficacy results for the full analysis set, improvement was observed in the active tablet group in subgroup analysis. In women, skin moisture content on the back of the hand increased significantly. In subjects 40 years of age and older, skin thickness on the cheek and skin moisture content on the back of the hand increased significantly. In subjects with TEWL of the mean value or more, TEWL in the cheek and the back of the hand increased significantly. Conclusions Our results demonstrated that the test tablet improved skin moisture of the cheek and back of the hand in some healthy Japanese adults with skin moisture problems. The consumption of the active tablet was found to be safe in this study. Trial registration　UMIN000038977 Foundation　Shinnihonseiyaku Co., Ltd.

Objectives　Perilla, a traditional functional herb used in Asia for its antioxidant, anti-inflammatory, and anti-allergic effects, has been shown to improve frequent urination and related symptoms in an animal model. Here, our objective was to investigate the influence of Perilla extract on lower urinary tract symptoms（LUTS）and sleep in Japanese adults. Methods　Twenty eligible Japanese men and women in this randomized double-blind placebo-controlled crossover study were given Perilla extract（PE）or placebo tablets for 4 weeks. LUTS and quality of sleep were investigated using the overactive bladder symptom score, micturition diary, and activity-based sleep monitor before and after the intake of the tablets. Results The total score and subscore of nocturia frequency in overactive bladder symptom score decreased significantly after the intake of PE tablets for 2 weeks compared with before tablet intake. A significant improvement in sleep efficiency was observed in the PE group compared with placebo group after ingestion for 4 weeks. Particularly, women in the PE group showed a significant improvement in the mean change in voided volume per micturition and number of daytime micturition compared with women in the placebo group. Conclusions　PE may be a useful option for alleviating LUTS and nocturnal awakening associated with bladder storage dysfunction.（UMIN-CTR/UMIN000033923）

Objective　Mulberry leaf containing 1-deoxynojirimycin（DNJ）is suggested to reduce postprandial blood glucose elevation by suppressing absorption of glucose. We conducted an intervention study with a food containing mulberry leaf powder to confirm the effect. Methods　A randomized, double-blind, placebo-controlled, crossover study was conducted in 30 healthy adult subjects with normal-high postprandial blood glucose level at 30 min（140-200 mg/dL）. They took 200 g of rice after ingesting of 100 mL water with test food containing 1.8 g of mulberry leaf powder （1.8 mg of DNJ）or placebo. The postprandial blood glucose level and insulin level were measured before and 30, 60, 90, 120 minutes after the intake of rice. Results　Ingestion of the test food containing mulberry leaf powder significantly reduced area under the curve（AUC（0-60 min））of blood glucose level, maximum concentration of blood glucose level（Cmax）and blood glucose level at 30 min compared with placebo. Conclusions　This study suggests that ingestion of mulberry leaf powder containing DNJ reduce the postprandial blood glucose level. （UMIN ID: UMIN000039508）

Objectives　The aim of this study was to evaluate the effect of S-IgA secretion in saliva by chewing gum. Methods　Twenty healthy subjects participated in a randomized, open, crossover trial. Subjects ingested three test foods（tablet, tasteless gum, xylitol-containing gum）or nothing and collected saliva over time on different days per each samples. The collected saliva was measured weight, protein abundance and S-IgA secretion. Results　S-IgA secretion and saliva volume were significantly increased just after intake the xylitol-containing gum. The tablet and the tasteless gum group also increased compared to the non-ingestion group, but not as much as the xylitol-containing gum group. In addition, S-IgA secretion and saliva volume were significantly increased compared to resting saliva while taking tasteless gum or xylitol-containing gum. Conclusions　In conclusion, mastication gum increased saliva volume and S-IgA secretion. Furthermore, the effect lasted during mastication. （UMIN000041497）

サブグループ解析の使い方が誤っている例を散見するため，今回，緊急にコラムで解説することにしました。年齢によるサブグループ解析とは，たとえば60 歳以上の高齢者と60 歳未満の非高齢者に分けて解析することです。ところが，60 歳以上の高齢者しか解析していない例を見受けます。高齢者で良い結果が得られたからでしょう。しかし，もしそうであるなら，非高齢者は悪い結果のはずです。悪い結果を除外することは，spin（スピン）と言って，「いいとこ取り」の可能性があります。以下に詳しく解説します。